Use of a chemically-stabilized chlorite solution for inhibiting an antigen-specific immune response

Abstract

Methods of using a stabilized chlorite solution to inhibit antigen-specific immune responses are disclosed. The stabilized chlorite solution, when administered to a mammal in need thereof, can prevent the presentation of antigens by antigen presenting cells. The stabilized chlorite solution therefore is useful in treating, inter alia, auto-immune diseases, treating diseases caused by an inappropriate immune response, treating lymphoproliferative disease and in inhibiting rejection in transplant patients.

Description

FIELD OF THE INVENTION[0001]The present invention relates to the use of a stabilized chlorite solution to inhibit antigen-specific immune responses. The stabilized chlorite solution inhibits antigen-specific immune responses by impeding antigen presentation by antigen presenting cells. The stabilized chlorite solution therefore is useful in treating diseases caused by or associated with unwanted or inappropriate antigen-specific immune responses including, for example, auto-immune diseases, hepatitis B and C, chronic hepatitis, chronic obstructive pulmonary disease, systemic lupus erythemotosus and in preventing rejection in organ transplant and graft patients (graft versus host disease). The stabilized chlorite solution also is useful in treating lymphoma, specifically, follicular non-Hodgkin's lymphoma.BACKGROUND OF THE INVENTION[0002]A feature common to an immune response is the recognition of an antigen (either foreign or self, but perceived as foreign), and subsequent processin...

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Benefits of technology

[0034]Other objects, features and advantages of the present invention will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating preferred embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description.

Problems solved by technology

Successful binding of the TCR to the presented antigenic epitope results in a cascade of events.

Inappropriate immune responses occur in a similar manner, however, and can lead to undesirable T cell proliferation, unwanted lymphokine secretion, and a state of autoimmunity.

This type of reactivity is observed, for example, in rejection of non-self grafts, such as transplanted organs, and clearly is undesirable in such situations.

Reported mechanisms of immunosuppression that act by interfering with allorecognition (i.e., by depletion of graft antigen, inhibition of APC function, blockade of surface receptor / co-receptor molecules, etc.) are ineffective for preventing or reducing the severity of an allogeneic response, however, because of their toxic side effects and their short-term activity.

In addition, there are no reported treatment regimens that are effective in blocking the B7 / CD28 co-stimulatory interaction.

Tolerance to self antigens sometimes breaks down, however, causing autoimmunity, where T or B cells (or both), as well as various cytokines of a mammal, react against and destroy the antigens in the mammal's own tissues.

In addition, mammals frequently show inappropriate immune responses to foreign antigens, causing an overstimulation or overactivation of the immune system that results in damage to normal, healthy tissue.

Methods of modulating the immune response that attempt to interfere with the production of stimulated T cells after antigen presentation characteristically require administration of a large quantity of therapeutic agent, which can cause undesirable toxic side effects.

Moreover, while expansion of anti-self T cells are necessary for some autoimmune diseases, their presence alone is not sufficient to cause all auto immune responses.

Thus, preventing anti-self T cell proliferation alone may be ineffective in treating many autoimmune diseases.

In the case of organ transplants and tissue grafting, it is not advantageous to initiate an immune response to the foreign antigens of the transplanted or grafted organ.

Graft acceptance is limited, however, by the tolerance of the recipient to these cytotoxic chemicals, many of which are similar to anticancer (antiproliferative) agents.

Likewise, when using cytotoxic antimicrobial agents, particularly antiviral drugs, or when using cytotoxic drugs for autoimmune disease therapy, e.g., in treatment of systemic lupus erythematosis, one serious limitation is the toxic effects to the bone marrow and the hematopoietic cells of the body.

A further limitation is the inability of the cytotoxic agents to induce an immunological tolerance to the foreign antigens.

Toxic side effects to normal tissues and cells also can limit the efficacy of most forms of nonsurgical cancer therapy, such as external irradiation and chemotherapy, because of the limited specificity of these treatment modalities for cancer cells.

This limitation is also of importance when anti-cancer antibodies are used for targeting toxic agents, such as isotopes, drugs, and toxins, to cancer sites, because, as systemic agents, the antibodies also circulate to sensitive cellular compartments such as the bone marrow.

Preventing secretion of cytokines and / or inhibiting antigen presentation in antigen presenting cells (macrophages, dendritic cells, etc.), however, has not been reported as useful (or not useful) in ameliorating these side effects.

Conventional immunosuppression also is ineffective in treating organ transplant and graft rejection.

First, most immunosuppressive agents, such as antiproliferative and corticosteroids, display a low immunosuppressive efficacy.

Second, excessive amounts of immunosuppressive agents, such as the monoclonal antibody OKT3, may produce toxic effects on T and B cells, leading to emergence of occult viral infections in, or neoplastic diseases of, lymphoid cells.

Third, toxic effects on organs not belonging to the immune system result from administration of large doses of immunosuppressive agents such as cyclosporine.

Follicular lymphoma, progresses relatively slowly over time and requires little therapy, except when it causes the patient discomfort or develops a life-threatening complication.

Although falling in the low grade category of lymphoma, follicular lymphoma can not be cured given current therapeutic considerations, and is ultimately universally fatal.

Anti-idiotypic therapy has not been adopted, however, because, since the anti-idiotypic antibodies are made from the patient's own B cells (which have the inherent capacity to modify their structure), the B cell tumors also have the ability to somatically mutate their antigen binding site (i.e., idiotype) thus making them impervious to anti-idiotypic therapy.

Despite the numerous treatment regimens for follicular lymphoma, and despite the recent advancements in cancer biotherapy trials, there have been no significant improvements in the management of lymphomas.

Inhibiting an inappropriate immune response and inhibiting and / or preventing antigen presentation, while advantageous in ameliorating autoimmune disorders, allergic responses, transplant rejections, etc., has the disadvantage of reducing the immune system's ability to fight off infections.

There are no known therapies capable of inhibiting an antigen-specific immune response, while at the same time stimulating phagocytic activity.

Notably, however, the method is unsuitable for use with blood products containing red blood corpuscles, i.e., of leukocytes, blood platelets, coagulation factors and globulins.

However, these documents do not report the use of these chlorite matrices for intravenous administration for inhibiting an antigen-specific immune response.

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